Neurons Behind Sustained Pain Identified

Researchers have identified a set of neurons responsible for sustained pain and resulting pain-coping behaviours in mice.

The findings by researchers at Harvard Medical School in the US point to the existence of separate neural pathways that regulate threat avoidance versus injury mitigation.

The study, published in the journal Nature, can inform new ways to gauge the efficacy of candidate pain therapies by assessing behaviours stemming from different pathways.

The study identified the nerve-signalling pathway behind the deep, sustained pain that sets in immediately following injury. The findings also shed light on the different pathways that drive reflexive withdrawal to avoid injury and the subsequent pain-coping responses.

Clinical observations of patients with neurological damage together with past research have outlined the distinct brain regions that differentiate between the reflexive withdrawal from a skin prick, for example, and the long-lasting pain arising from tissue injury caused by the pinprick.

The new study, however, is the first one to map out how these responses arise outside the brain.

The findings, based on experiments in mice, put into question the validity of current experimental approaches for assessing the efficacy of candidate pain-relief compounds.

Most current methods rely on measuring the initial, reflexive response that serves to avert tissue injury, rather than on measuring the lasting pain that arises from actual tissue damage, the researchers said.

Some drug compounds that might have been successful in assuaging the sustained pain - the lasting sensation of pain that immediately follows injury - could have been dismissed as ineffective because they were assessed against the wrong outcome.

The ongoing opioid crisis has created an acute and pressing need to develop new pain treatments, and our findings suggest that a more tailored approach to assessing pain response would be to focus on sustained pain response rather than reflexive protective withdrawal. All these years, researchers may have been measuring the wrong response. Indeed, our results could explain, at least in part, the poor translation of candidate treatments from preclinical studies into effective pain therapies.

Qiufu Ma, Professor at Harvard Medical School.

The team focused on a set of neurons called Tac1 emanating from the so-called dorsal horn, a cluster of nerves located at the lower end of the spinal cord that transmit signals between the brain and the rest of the body.

In a series of experiments, the team assessed pain response in two groups of mice -- one with intact Tac1 neurons and another with chemically disabled Tac1 neurons.

Mice with inactivated Tac1 neurons had normal withdrawal reflexes when exposed to a painful stimulus.

They showed no notable differences in their withdrawal from pricking or exposure to heat and cold, researchers said.

However, when the researchers injected the animals with burn-inducing mustard oil, they did not engage in the typical paw licking that animals perform immediately following injury.

By contrast, mice with intact Tac1 neurons engaged in vigorous and prolonged paw licking to assuage the pain, researchers said.

These observations confirm that Tac1 neurons are critical for pain-coping behaviours stemming from sustained irritation or injury but that they play no role in reflexive-defensive reactions to external threats, they said.